Cardiovascular adverse events associated with second generation Bruton tyrosine kinase inhibitor therapy: A systematic review and meta-analysis.
Authors: Ekaterina Proskuriakova, Ranjit Jasaraj, Suman Gaire, Anuradha Raut, Vijay Ketan Reddy, Dhan Shrestha, Iuliia Kovalenko, Paramjeet Grewal Khosla
Journal: Journal of Clinical Oncology (2023)

e15109 Background: Cardiovascular adverse events (CVAE) is a frequent adverse effect of first-generation bruton tyrosine kinase inhibitor (BTKi) that significantly reduce the usage of these medications. This led to the development of second-generation BTKi (acalbrutinib and zanubrutinib) that are more selective and potent with presumably better safety profile than first-generation. CVAE associated with second-generation BTKis in the clinical practice has been sporadically reported. Hence, we attempted to pool the reported CVAE in this meta-analysis. Methods: Systematic searches of PubMed, PubMed Central, Cochrane library for clinical trials, Scopus, and Embase were conducted from inception until January 14, 2023. This meta-analysis performed per PRISMA protocol and registered in PROSPERO database (CRD42023392406). All randomized clinical trials including acalabrutinib or zanabrutinib in treatment arm with standard of care as control arms were included. The literature found from search engines were imported in the covidence platform and screened independently by 2 reviewers in title/abstract and full text phase. Conflicts were resolved by a third reviewer. Included studies were thoroughly reviewed by all reviewers and data from them extracted in a Microsoft Excel. Analysis performed using RevMan 5.4 meta-analysis software. Odds ratio was used as an effect measure with 95% confidence intervals (CI) using random effect model. Results: A total of ten trials (with 3048 patients, 1710 in treatment arm) were included in this meta-analysis. Cardiovascular events leading to death were reported in 4 studies. In the second generation BTKis group cardiovascular death was 0.94% (7/744), while in the control group it was 1.7% (12/705). Using the random effect model, a pooled analysis on death due to cardiovascular events were statistically insignificant across two groups (OR 0.46, 95% CI 0.19 to 1.11; n = 2039; I 2 = 57%). Similarly, pooled analysis for any bleeding/hemorrhage from eight studies (OR 2.12, 95% CI 0.91 to 4.97; n = 2611; I 2 = 93%), major bleeding from seven studies (OR 1.12; 95% CI 0.66 to 1.89, n = 2658, I 2 = 28%), acute coronary syndrome from four studies (OR 3.13; 95% CI 0.65 to 15.13, n = 1585, I 2 = 0%) were also statistically not significant. Conclusions: Treatment with acalabrutinib and zanabrutinib did not show any significant differences in cardiovascular events between the group when compared with standard treatment as a control group, meta-analyzing the data from published trials. As there is no evidence of worse cardiovascular outcomes or superiority of the second-generation BTKis compared to standard treatments in terms of safety based on available evidence, further large-scale controlled trials are required to support that new-generation BTKis are superior in safety and better tolerated.